Development of a Web-Based Oxygenation Dashboard for Preterm Neonates: A Quality Improvement Initiative.

BACKGROUND: Preterm neonates are extensively monitored to require strict oxygen target attainment for optimal outcomes. In daily practice, detailed oxygenation data are hardly used and crucial patterns may be missed due to the snapshot presentations and subjective observations. This study aimed to develop a web-based dashboard with both detailed and summarized oxygenation data in real-time and to test its feasibility to support clinical decision making. METHODS: Data from pulse oximeters and ventilators were synchronized and stored to enable real-time and retrospective trend visualizations in a web-based viewer. The dashboard was designed based on interviews with clinicians. A preliminary version was evaluated during daily clinical rounds. The routine evaluation of the respiratory condition of neonates (gestational age < 32 weeks) with respiratory support at the NICU was compared to an assessment with the assistance of the dashboard. RESULTS: The web-based dashboard included data on the oxygen saturation (SpO2), fraction of inspired oxygen (FiO2), SpO2/FiO2 ratio, and area < 80% and > 95% SpO2 curve during time intervals that could be varied. The distribution of SpO2 values was visualized as histograms. In 65% of the patient evaluations (n = 86) the level of hypoxia was assessed differently with the use of the dashboard. In 75% of the patients the dashboard was judged to provide added value for the clinicians in supporting clinical decisions. CONCLUSIONS: A web-based customized oxygenation dashboard for preterm neonates at the NICU was developed and found feasible during evaluation. More clear and objective information was found supportive for clinicians during the daily rounds in tailoring treatment strategies.

Cognitive Functioning in Survivors of Hematopoietic Stem Cell Transplantation Compared With a Matched General Population Sample-The Maastricht Observational Study of Late Effects After Stem Cell trAnsplantation Study.

Although cognitive problems can recover over time, a subgroup of hematopoietic stem cell transplantation (HCT) survivors experience persistent cognitive problems in the long term. Despite these implications, studies assessing cognitive functioning in HCT survivors are limited. The aim of the present study was (1) to quantify the prevalence of cognitive impairment in patients treated with HCT who survived at least 2 years and to compare these with a matched reference group representing the general population; (2) to identify potential determinants of cognitive functioning within the HCT survivor group. Within the single-center Maastricht Observational study of late effects after Stem cell trAnsplantation, cognitive performance was assessed by a neuropsychological test battery divided into 3 cognitive domains: memory, information processing speed, and executive function and attention. An overall cognition score was calculated as the average of the domain scores. A total of 115 HCT survivors were group-matched on a 1:4 ratio to the reference group by age, sex, and level of education. Regression analyses adjusted for different sets of covariates including demographic and health- and lifestyle-related factors were used to test for differences in cognition between HCT survivors and the reference group resembling the general population. A limited set of clinical characteristics (diagnosis, type of transplant, time since treatment, conditioning regimen with total body irradiation and age at time of transplantation) were assessed as potential determinants of neurocognitive dysfunction among HCT survivors. Cognitive impairment was defined as scores in the cognitive domains < -1.5 standard deviation (SD) from what can be expected based on someone's age, sex, and education. The mean age at time of transplantation was 50.2 (SD ± 11.2) years, and the mean number of years after transplant was 8.7 (SD ± 5.7) years. The majority of HCT survivors were treated with autologous HCT (n = 73 [64%]). The prevalence of cognitive dysfunction was 34.8% in HCT survivors and 21.3% in the reference group (p = .002.) When adjusted for age, sex, and level of education, HCT survivors had a worse overall cognition score (b = -0.35; 95% confidence interval [CI], -0.55 to -0.16; p < .001), translating into 9.0 years of higher cognitive age. Analyses of specific cognitive domain scores showed that HCT survivors scored worse on memory (b = -0.43; 95% CI, -0.73 to -0.13; p = .005), information processing speed (b = -0.33; 95% CI, -0.55 to -0.11; p = .003), and executive function and attention (b = -0.29; 95% CI, -.55 to -.03; p = .031) than the reference group. The odds of cognitive impairment were on average 2.4 times higher among HCT survivors than the reference group (odd ratio = 2.44; 95% CI, 1.47-4.07; p = .001). Within the HCT survivor group none of the tested clinical determinants of cognitive impairment were significantly associated with cognition. This cohort study showed evidence for worse cognitive functioning in HCT survivors encompassing all three cognitive domains, respectively memory, information processing speed, and executive and attention compared to a reference group that represents the general population translating into nine years of faster cognitive ageing in HCT survivors than can be expected based on their chronological age. It is important to increase awareness for signs of neurocognitive dysfunction after HCT in clinicians and HCT survivors.

Quantification of stress exposure in very preterm infants: Development of the NeO-stress score.

BACKGROUND: Stress during treatment at the Neonatal Intensive Care Unit (NICU) has long-term negative consequences on preterm infants' development. AIMS: We developed an instrument suited to validly determine the cumulative stress exposure for preterm infants in a NICU. STUDY DESIGN: This survey study made use of two consecutive questionnaires. SUBJECTS: NICU nurses and physicians from the nine NICUs in the Netherlands. OUTCOME MEASURES: First, respondents rated the relevance of 77 items encompassing potentially stressful procedures, commented on their comprehensibility and the comprehensiveness of the list. We calculated the content validity per item (CVI-I) and included only the relevant items in a second questionnaire in which the participants rated the stressfulness from 0 (not stressful) to 10 (extremely stressful). A stressfulness index - representing the median score - was calculated for each included item. RESULTS: Based on the CVI-I of the 77 items, step 1 resulted in 38 items considered relevant to quantify stress in preterm infants during the first 28 days of life. This list of 38 items exists of 34 items with a CVI-I if 0.78 or higher, one of these items was split into two items, and three items were added to improve comprehensiveness. The stressfulness index ranged from five to nine. CONCLUSIONS: The NeO-stress score consists of stressful items including their severity index and was developed to determine cumulative stress exposure of preterm infants. Evaluating the cross-cultural validity, correlating it to behavioural and biological stress responses, and evaluating its ability to predict preterm infants at risk for the negative effects following stress might expand the possibilities for this instrument.

[Glucocorticoid treatment in pregnancy; is caution the mother of wisdom?] / Behandeling met glucocorticoïden in de zwangerschap.

Timely prenatal, maternally administered, corticosteroids improve the outcome of preterm newborns. The general aim should therefore be optimal identification of actual imminent preterm birth to provide protection of all preterm infants that are at risk of a substantial level of post-natal morbidity. Unnecessary use of maternal corticosteroids by inadequate estimate of imminent preterm birth, now seems associated with mental and behavioural problems in the offspring during the life course, which calls for a more restricted use. Opportunities to reduce futile use of maternal corticosteroids in case of preterm birth might be found in better timing of administration, improved selection of women at risk and by potential restraint re-use at later gestational ages. Timing and selection can be further improved by the development of better (non-invasive) predictors to pinpoint those women who actual will deliver within 48 hours. Future prospective studies should provide additional evidence to improve antenatal corticosteroid administration.

Dissecting transcriptional amplification by MYC.

Supraphysiological MYC levels are oncogenic. Originally considered a typical transcription factor recruited to E-boxes (CACGTG), another theory posits MYC a global amplifier increasing output at all active promoters. Both models rest on large-scale genome-wide "-omics'. Because the assumptions, statistical parameter and model choice dictates the '-omic' results, whether MYC is a general or specific transcription factor remains controversial. Therefore, an orthogonal series of experiments interrogated MYC's effect on the expression of synthetic reporters. Dose-dependently, MYC increased output at minimal promoters with or without an E-box. Driving minimal promoters with exogenous (glucocorticoid receptor) or synthetic transcription factors made expression more MYC-responsive, effectively increasing MYC-amplifier gain. Mutations of conserved MYC-Box regions I and II impaired amplification, whereas MYC-box III mutations delivered higher reporter output indicating that MBIII limits over-amplification. Kinetic theory and experiments indicate that MYC activates at least two steps in the transcription-cycle to explain the non-linear amplification of transcription that is essential for global, supraphysiological transcription in cancer.

Levantamento parasitológico realizado em munícipes do interior do estado de São Paulo (Brasil) entre os anos de 1957 a 1986

Parasitism caused by protozoa and helminths is a serious public health problem, affecting millions of individuals worldwide, especially in underdeveloped and developing countries. From this perspective, a parasitological survey was conducted in 37 cities in the interior of the state of São Paulo. This study focused mainly on old places such as schools and rural and urban health units in the interior of the State of São Paulo between 1957 and 1986. The objective of this study was to conduct a comprehensive survey on the data found to diagnose the occurrence of parasitic diseases in the city. Population at that time, according to their rural and urban origin, age and gender. Thus, the proposal is to make the generated data available to all interested parties in an organized and systematized manner and to discuss the reality faced by the population regarding the current public policies in Brazil relating the sanitary conditions with the occurrence of endoparasites. According to the survey conducted in the municipalities studied, 274,487 occurrences of individuals positive for endoparasites were obtained from 391,633 samples collected. The highest frequency was found in children aged 1 to 10 years with 146,090 cases, accounting for 37,302% of the infected population. The percentage of parasitized individuals decreases with increasing age.

Os quadros de parasitismos causados por protozoários e helmintos constituem sérios problemas de saúde pública, por afetarem milhões de indivíduos em todo o mundo, sobretudo, nos países subdesenvolvidos e em desenvolvimento. Sob esta perspectiva foi realizado um levantamento parasitológico em 37 cidades do interior do Estado de São Paulo. Este estudo contemplou principalmente antigos locais como as escolas e unidades de saúde rurais e urbanas do interior do Estado de São Paulo entre os anos de 1957 e 1986. O objetivo deste trabalho foi realizar um levantamento abrangente nos dados encontrados para diagnosticar a ocorrência de parasitoses na população da época, segundo sua origem rural e urbana, a faixa etária e o gênero. Dessa forma, a proposta é tornar os dados gerados disponíveis a todos os interessados de forma organizada e sistematizada e discutir a realidade enfrentada pela população frente às políticas públicas vigentes no Brasil relacionando as condições sanitárias com a ocorrência de endoparasitoses. Segundo o levantamento realizado nos municípios estudados, obteve-se 274.487 ocorrências de indivíduos positivos para endoparasitas a partir de 391.633 amostras coletadas. A maior frequência foi encontrada em crianças de 1 a 10 anos com 146.090 casos, sendo estes responsáveis por 37.302% da população infectada. A porcentagem de indivíduos parasitados diminui de acordo com o aumento da idade.

Black TiO2 nanotubes: Efficient electrodes for triggering electric field-induced stimulation of stem cell growth.

TiO2 nanostructures represent a key platform for biomedical applications, due to the combination of biocompatibility and high surface area. Especially TiO2 nanotube layers have been widely investigated due to controllable nanotopographic effects as well as for electrodes in electrostimulation experiments. In the present work we produce Ar/H2-reduced 'black' TiO2 nanotube arrays with a strongly enhanced electrical conductivity and explore their interaction with mesenchymal stem cells when used as electrodes to apply electric fields (EF) across the cells. While we observe no significant change in cell adhesion and their focal contact formation on these high conductivity nanotubes, we do observe a rapid stem cell response when EF is engaged using the 'black' TiO2 nanotube arrays as electrodes. Compared to as-formed nanotube arrays, a faster stem cell growth was observed and a lower EF intensity caused an intracellular calcium level elevation. Our results indicate that the increased conductivity in TiO2 nanotubes significantly enhances the early stem cell response to minimal electric field stimuli. STATEMENT OF SIGNIFICANCE: The use of TiO2 nanostructures in biomedical applications is widely investigated, especially considering the nanostructured surface influence on the biomaterial-cell interactions. We have previously shown that an applied electric field (EF) on stem cells grown on TiO2 nanotubes leads to synergistic osteogenic stimulation in the absence of biochemical bone-inducing supplements. Here we report that black (i.e. highly conductive nanotubes obtained by reduction treatments) TiO2 nanotubes enable short-time EF effects on stem cells: we observe a faster stem cell growth and a significantly enhanced early stem cell response to minimal EF stimuli. The application of such nanostructures under electric field is promising for therapeutic interventions for bone regeneration and tissue engineering approaches.

Medication adherence among patients with chronic diseases: a survey-based study in pharmacies.

BACKGROUND: Poor adherence to medication leads to worsening of the disease, increased mortality and substantial rise in health care costs. AIM: It was our aim to evaluate drug adherence and influencing factors in a cohort of non-selected adult pharmacy customers with various chronic diseases and following long-term treatment. DESIGN AND METHODS: We conducted an 8 week anonymized survey in 152 German pharmacies using the Morisky Medication Adherence Scale to measure medication adherence and a questionnaire comprising questions on multiple factors with potential impact on adherence. Depression was assessed applying the Patient Health Questionnaire-9. RESULTS: In total, 1192 patients were included showing an overall adherence rate of 59.1%. A positive association to drug adherence was found in univariate analysis for non-smoking status, retirement, less disease related complaints, positive belief in drug effects, comprehensive knowledge about the disease and high quality of care by the physician and pharmacist. Multivariate regression analysis revealed that no or minimal depression (odds ratio (OR) 2.3, 95% confidence interval (CI) 1.7-3.0), higher patient age (>63 years) (OR 2.2, CI 1.7-2.8), high perceived importance of the medication (OR 2.0, CI 1.5-2.6), good tolerability of the medication (OR 2.0, CI 1.2-3.5) and drug effect as expected or better (OR 1.6, CI 1.1-2.3) were positively correlated with adherence. CONCLUSIONS: Suboptimal adherence to medication is common in pharmacy customers with chronic diseases. The determined factors influencing adherence may help to identify patients at risk for nonadherence and support the need of improvement in physicians' communication with patients to achieve adequate adherence rates.

Intravenous cyclophosphamide pulse therapy in interstitial lung disease associated with systemic sclerosis in a retrospective open-label study: influence of the extent of inflammation on pulmonary function.

Interstitial lung disease (ILD) is the primary cause of death in patients with systemic sclerosis (SSc). It is thought that chronic inflammation is a key component in SSc-ILD. Treatment, such as cyclophosphamide (CYC), targets this inflammation. We hypothesized that treatment with CYC might be more effective in the inflammatory phase. Therefore, we analyzed whether the extent of inflammation, as assessed by the proportion of ground glass compared to fibrosis, SSc disease duration, the extent of ILD, or baseline diffusion capacity of the lungs (DLCO) < 60%, modifies the effect of intravenous CYC pulse therapy (750 mg/m2) on pulmonary function (as measured by FVC, DLCO) in SSc-ILD patients, after 12, 24, and 36 months. Consecutive patients with SSc-ILD receiving CYC pulses between 2003 and 2015 were included. Pulmonary function tests were performed at 0, 6, 12, 24, and 36 months. There were 75 patients included. Forced vital capacity (FVC) (86% of predicted) and DLCO (42% of predicted) were stable after 12, 24 and 36 months of follow-up (p > 0.05). Forty-four patients completed 12 cycles of CYC. For the extent of ILD, proportion of ground glass compared to fibrosis, SSc disease duration, and baseline DLCO, there were no differences (all p > 0.05) in the course of FVC and DLCO. Treatment with CYC followed by maintenance therapy stabilizes pulmonary function in patients with SSc-ILD over a 3-year period. The extent of ILD, proportion of ground glass, SSc disease duration, and baseline DLCO < 60% did not influence the effect of CYC on pulmonary function.

An Approach to Greater Specificity for Glucocorticoids.

Glucocorticoid steroids are among the most prescribed drugs each year. Nonetheless, the many undesirable side effects, and lack of selectivity, restrict their greater usage. Research to increase glucocorticoid specificity has spanned many years. These efforts have been hampered by the ability of glucocorticoids to both induce and repress gene transcription and also by the lack of success in defining any predictable properties that control glucocorticoid specificity. Correlations of transcriptional specificity have been observed with changes in steroid structure, receptor and chromatin conformation, DNA sequence for receptor binding, and associated cofactors. However, none of these studies have progressed to the point of being able to offer guidance for increased specificity. We summarize here a mathematical theory that allows a novel and quantifiable approach to increase selectivity. The theory applies to all three major actions of glucocorticoid receptors: induction by agonists, induction by antagonists, and repression by agonists. Simple graphical analysis of competition assays involving any two factors (steroid, chemical, peptide, protein, DNA, etc.) yields information (1) about the kinetically described mechanism of action for each factor at that step where the factor acts in the overall reaction sequence and (2) about the relative position of that step where each factor acts. These two pieces of information uniquely provide direction for increasing the specificity of glucocorticoid action. Consideration of all three modes of action indicate that the most promising approach for increased specificity is to vary the concentrations of those cofactors/pharmaceuticals that act closest to the observed end point. The potential for selectivity is even greater when varying cofactors/pharmaceuticals in conjunction with a select class of antagonists.

[When is a venous blood gas analysis sufficient in the emergency department?] / Wanneer volstaat een veneuze bloedgas op de SEH?

Blood gas analysis plays an important role in the initial assessment of a patient in the emergency ward. We present three different patient cases to illustrate when to opt for a venous or an arterial blood gas analysis. Arterial punctures are more painful and carry a higher risk of complications compared to venous punctures. It is possible to use a venous blood gas to screen for acute acid/base disturbances. Ventilatory compensation or anion gap cannot be calculated reliably with a venous blood gas. On the other hand, the diagnosis diabetic keto-acidosis can be made with a venous blood gas; this mode of sampling can also be used for lactate measurement at the emergency department as an independent prognostic marker for mortality. Venous blood gas analyses are not able to assess oxygenation. Pulse oximetry is a non-invasive alternative for arterial blood gas sampling. The use of a venous blood gas to assess a patient's ventilation is limited, whereas it can be used to diagnose carbomonoxide intoxication or methaemoglobinaemia.

Simulation fails to replicate stress in trainees performing a technical procedure in the clinical environment.

INTRODUCTION: Simulation-based training (SBT) has become an increasingly important method by which doctors learn. Stress has an impact upon learning, performance, technical, and non-technical skills. However, there are currently no studies that compare stress in the clinical and simulated environment. We aimed to compare objective (heart rate variability, HRV) and subjective (state trait anxiety inventory, STAI) measures of stress theatre with a simulated environment. METHODS: HRV recordings were obtained from eight anesthetic trainees performing an uncomplicated rapid sequence induction at pre-determined procedural steps using a wireless Polar RS800CX monitor © in an emergency theatre setting. This was repeated in the simulated environment. Participants completed an STAI before and after the procedure. RESULTS: Eight trainees completed the study. The theatre environment caused an increase in objective stress vs baseline (p = .004). There was no significant difference between average objective stress levels across all time points (p = .20) between environments. However, there was a significant interaction between the variables of objective stress and environment (p = .045). There was no significant difference in subjective stress (p = .27) between environments. DISCUSSION: Simulation was unable to accurately replicate the stress of the technical procedure. This is the first study that compares the stress during SBT with the theatre environment and has implications for the assessment of simulated environments for use in examinations, rating of technical and non-technical skills, and stress management training.

[A man with slowly progressive dyspnea on exertion]. / Een man met langzaam progressieve dyspnée d'effort.

A 42-year-old man with a medical history of liver cirrhosis and portal hypertension was admitted to the hospital because of slowly progressive shortness of breath and hypoxemia. The diagnosis hepatopulmonary syndrome was confirmed by a pulmonary perfusion scan with 99m Tc-albumin. The scan showed a right-left shunt, because the 99m Tc-albumin transited the lungs and appeared in the brain, the thyroid gland, the kidneys and the spleen. The patient received a liver transplantation, which is considered the only definitive treatment.

Kinetically Defined Mechanisms and Positions of Action of Two New Modulators of Glucocorticoid Receptor-regulated Gene Induction.

Most of the steps in, and many of the factors contributing to, glucocorticoid receptor (GR)-regulated gene induction are currently unknown. A competition assay, based on a validated chemical kinetic model of steroid hormone action, is now used to identify two new factors (BRD4 and negative elongation factor (NELF)-E) and to define their sites and mechanisms of action. BRD4 is a kinase involved in numerous initial steps of gene induction. Consistent with its complicated biochemistry, BRD4 is shown to alter both the maximal activity (Amax) and the steroid concentration required for half-maximal induction (EC50) of GR-mediated gene expression by acting at a minimum of three different kinetically defined steps. The action at two of these steps is dependent on BRD4 concentration, whereas the third step requires the association of BRD4 with P-TEFb. BRD4 is also found to bind to NELF-E, a component of the NELF complex. Unexpectedly, NELF-E modifies GR induction in a manner that is independent of the NELF complex. Several of the kinetically defined steps of BRD4 in this study are proposed to be related to its known biochemical actions. However, novel actions of BRD4 and of NELF-E in GR-controlled gene induction have been uncovered. The model-based competition assay is also unique in being able to order, for the first time, the sites of action of the various reaction components: GR < Cdk9 < BRD4 ≤ induced gene < NELF-E. This ability to order factor actions will assist efforts to reduce the side effects of steroid treatments.

Molecular drug susceptibility testing in the Netherlands: performance of the MTBDRplus and MTBDRsl assays.

BACKGROUND: The performance of molecular drug susceptibility testing in countries with a low prevalence of drug resistance, such as the Netherlands, has not been adequately studied. OBJECTIVE: To evaluate the diagnostic accuracy of the GenoType(®) MTBDRplus and MTBDRsl assays to detect resistance to first- and second-line anti-tuberculosis drugs in the context of a nationwide screening programme in the Netherlands. RESULTS: The MTBDRplus assay had a sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of 100%, 99%, 80% and 100% for detecting rifampicin resistance. The sensitivity, specificity, PPV and NPV of either a katG or inhA mutation for detecting isoniazid resistance were 88%, 100%, 100% and 99%. The MTBDRsl assay had a sensitivity, specificity, PPV and NPV of 100%, 99%, 83%, and 100% for detecting moxifloxacin resistance; 62%, 71%, 58% and 74%, respectively, for detecting ethambutol resistance; 86%, 99%, 86% and 99% for detecting amikacin resistance; and 50%, 96%, 71% and 91% for detecting capreomycin resistance. CONCLUSION: The MTBDRplus and MTBDRsl assays may aid in decision making in tuberculosis treatment in low-level drug resistance settings and should preferably be used to exclude resistance.

Theory of partial agonist activity of steroid hormones.

The different amounts of residual partial agonist activity (PAA) of antisteroids under assorted conditions have long been useful in clinical applications but remain largely unexplained. Not only does a given antagonist often afford unequal induction for multiple genes in the same cell but also the activity of the same antisteroid with the same gene changes with variations in concentration of numerous cofactors. Using glucocorticoid receptors as a model system, we have recently succeeded in constructing from first principles a theory that accurately describes how cofactors can modulate the ability of agonist steroids to regulate both gene induction and gene repression. We now extend this framework to the actions of antisteroids in gene induction. The theory shows why changes in PAA cannot be explained simply by differences in ligand affinity for receptor and requires action at a second step or site in the overall sequence of reactions. The theory also provides a method for locating the position of this second site, relative to a concentration limited step (CLS), which is a previously identified step in glucocorticoid-regulated transactivation that always occurs at the same position in the overall sequence of events of gene induction. Finally, the theory predicts that classes of antagonist ligands may be grouped on the basis of their maximal PAA with excess added cofactor and that the members of each class differ by how they act at the same step in the overall gene induction process. Thus, this theory now makes it possible to predict how different cofactors modulate antisteroid PAA, which should be invaluable in developing more selective antagonists.

Kinetically-defined component actions in gene repression.

Gene repression by transcription factors, and glucocorticoid receptors (GR) in particular, is a critical, but poorly understood, physiological response. Among the many unresolved questions is the difference between GR regulated induction and repression, and whether transcription cofactor action is the same in both. Because activity classifications based on changes in gene product level are mechanistically uninformative, we present a theory for gene repression in which the mechanisms of factor action are defined kinetically and are consistent for both gene repression and induction. The theory is generally applicable and amenable to predictions if the dose-response curve for gene repression is non-cooperative with a unit Hill coefficient, which is observed for GR-regulated repression of AP1LUC reporter induction by phorbol myristate acetate. The theory predicts the mechanism of GR and cofactors, and where they act with respect to each other, based on how each cofactor alters the plots of various kinetic parameters vs. cofactor. We show that the kinetically-defined mechanism of action of each of four factors (reporter gene, p160 coactivator TIF2, and two pharmaceuticals [NU6027 and phenanthroline]) is the same in GR-regulated repression and induction. What differs is the position of GR action. This insight should simplify clinical efforts to differentially modulate factor actions in gene induction vs. gene repression.

Radiographic evaluation of factors affecting bearing dislocation in the domed lateral Oxford unicompartmental knee replacement.

BACKGROUND: The rate of bearing dislocation with the domed lateral Oxford Unicompartmental Knee Replacement (OUKR) in different series varies from 1% to 6% suggesting that dislocation is influenced by surgical technique. The aim of this study was to identify surgical factors associated with dislocation. METHODS: Aligned post-operative antero-posterior knee radiographs of seven knees that had dislocated and 87 control knees were compared. Component alignment and position and the alignment of the knee were assessed. All bearing dislocations occurred medially over the tibial wall. RESULTS: Knees that dislocated tended to be overcorrected: Compared with those that did not dislocate, they were in 2° less valgus (p=0.019) and the tibial components were positioned 2 mm more proximal (p<0.01). Although the relative position of the centre of the femoral component and the tibial component was the same (p=0.8), in the dislocating group the gap between the edge of the femoral component and the top of the wall in flexion was 3mm greater (p=0.019) suggesting that the components were internally rotated. CONCLUSIONS: To minimise the risk of dislocation it is recommended that the knee should not be overstuffed. This is best achieved by selecting the bearing thickness that just tightens the ligaments in full extension, and re-cutting the tibia if necessary. In addition to minimise the gap between the femoral and tibial components through which the bearing dislocates, the femoral component should be implanted in neutral rotation and should not be internally rotated. LEVEL OF EVIDENCE: Level IV.

The use of mode of action information in risk assessment: quantitative key events/dose-response framework for modeling the dose-response for key events.

The HESI RISK21 project formed the Dose-Response/Mode-of-Action Subteam to develop strategies for using all available data (in vitro, in vivo, and in silico) to advance the next-generation of chemical risk assessments. A goal of the Subteam is to enhance the existing Mode of Action/Human Relevance Framework and Key Events/Dose Response Framework (KEDRF) to make the best use of quantitative dose-response and timing information for Key Events (KEs). The resulting Quantitative Key Events/Dose-Response Framework (Q-KEDRF) provides a structured quantitative approach for systematic examination of the dose-response and timing of KEs resulting from a dose of a bioactive agent that causes a potential adverse outcome. Two concepts are described as aids to increasing the understanding of mode of action-Associative Events and Modulating Factors. These concepts are illustrated in two case studies; 1) cholinesterase inhibition by the pesticide chlorpyrifos, which illustrates the necessity of considering quantitative dose-response information when assessing the effect of a Modulating Factor, that is, enzyme polymorphisms in humans, and 2) estrogen-induced uterotrophic responses in rodents, which demonstrate how quantitative dose-response modeling for KE, the understanding of temporal relationships between KEs and a counterfactual examination of hypothesized KEs can determine whether they are Associative Events or true KEs.